DETAILED ACTION
Non-Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election of Group I claims 1-13 with a species glycoprotein C in the reply filed on 02/03/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)). The restriction/election is made final.
Status of Claims
3. Claims 1-34 filed on 08/08/2023 are pending.
4. Claims 14-34 are withdrawn from examination due to restriction/election.
5. Claims 1-13 are under examination in this office action.
Priority
6. This application is the U.S. national stage of International Patent Application No. PCT/US2022/015703, filed February 8, 2022, which claims the benefit of U.S. Provisional Application No. 63/200,011, filed February 9, 2021, and U.S. Provisional Application No. 63/263,528, filed November 4, 2021.
Information Disclosure Statement
7. The information disclosure statement (IDS) submitted on 08/08/2023 in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
8. The listing of references in the specification on pages 63-69 para [0172]- [0216]
is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Claim Objections
9. Claims 1, 8, 10 and 12 are objected to because of the following informalities:
Claims 1, and 8: In line 3, the claims 1, and 8 recite “an oncolytic HSV-1 or HSV-2” that is redundant and creates confusion and it is not clear why “an” is used when the claim has already recited HSV-1 or HSV-2 in lines 1-2. Applicant is required to delete “an oncolytic HSV-1 or HSV-2” in line 3.
Claims 10: In line 3, the claim 10 recite “an oncolytic HSV-2”, and applicant is required to delete it.
Claim 12: In line 2, the claim 12 recite “an oncolytic HSV-2, and”, and applicant is required to delete it.
Claim 1: In lines 2 and 3 “HSV1” need to be written as “HSV-1” by inserting a hyphen. Also please review other pending claims for the same typographical error.
Claim 7: In lines 2-3, “gE” need to be amended to the HSV-1 or HSV-2 glycoprotein E (gE). The claim reads ambiguous, in the current form the claim reads on that the extracellular CD47 domain is free of substantially free of gE.
Appropriate correction is required.
Claim Interpretation
10. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1: A composition comprising an oncolytic Herpes Simplex Virus Type 1 (HSV-1) or Herpes Simplex Virus Type 2 (HSV-2), wherein the oncolytic HSV-1 or HSV-2 is prepared by passaging at least twice an oncolytic HSV-1 or HSV-2 with immune sera having elevated levels of anti-HSV antibodies.
The instant claim 1 is interpreted to be directed to development of an antibody neutralization escape mutant oncolytic HSV (HSV-1 or HSV-2) obtained by passaging the viruses with anti-HSV-1 or anti-HSV-2 immune sera (anti-HSV antibodies) having elevated levels of anti-HSV antibodies. According to the instant specification (para [0007]) the HSV glycoproteins D (gD) and glycoprotein B (gB) contains many neutralizing epitopes against which neutralizing antibodies are present in the immune serum. The passages of the HSV virus in the immune serum and the propagation of the HSV in cell culture in the presence of the immune serum is known to result in mutations in the amino acids in the neutralizing epitopes leading to development of neutralization escape mutant HSV virus (See, instant specification (para [0010]) that are interpreted to be efficacious as oncolytic virus due to escape from neutralization.
Claim 8: A composition comprising an oncolytic Herpes Simplex Virus Type 1 or Herpes Simplex Virus Type 2 (HSV-2), wherein the oncolytic HSV-1 or HSV-2 is prepared by passaging at least twice an oncolytic HSV-1 or HSV-2 in a mixture of immune sera, wherein the mixture of immune sera is comprised of rat sera and human sera that has elevated levels of anti-HSV antibodies.
The instant claim 2 is interpreted to be directed to development of an antibody neutralization escape mutant oncolytic HSV (HSV-1 or HSV-2) by passaging in a mixture of immune sera, wherein the mixture of immune sera is comprised of rat sera and human sera that has elevated levels of anti-HSV antibodies. The mixture of immune rea from rat and human is interpreted to comprise neutralizing antibodies against diverse epitopes recognized by the different species to develop an HSV that escape a neutralization by broadly immune sera that has broad neutralization property to develop more neutralization efficacious HSV mutant virus.
Claim Rejections - 35 USC § 103
11. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
12. Claims 1, 5, 8-10 are rejected under 35 U.S.C. 103 as being unpatentable over Glorioso et al 2020 (WO2019232379A1, 12/05/2019), and further in view of Highlander et al 1987 (J Virol. 1987 Nov;61(11):3356–3364), Cairns et al 2014 (J Virol 88, 2014, 12612-22), and Rojas et al 1992 (Journal of virology, 66(6), 3368-3372), Wakimoto et al 2002 (Molecular Therapy, 5(3), 275-282), and Lewis et al 1982 (Journal of Virology, 42(1), 275-282).
Claim 1: A composition comprising an oncolytic Herpes Simplex Virus Type I (HSV-1) or Herpes Simplex Virus Type 2 (HSV-2), wherein the oncolytic HSV1 or HSV-2 is prepared by passaging at least twice an oncolytic HSVI or HSV-2 with immune sera having elevated levels of anti-HSV antibodies.
Glorioso et al 2020 (WO2019232379A1) disclosed oncolytic HSV comprising an antigenically-modified glycoprotein B (gB) and/or an antigenically-modified glycoprotein D (gD) protein, wherein one or more major epitopes of gB and/or gD reactive with one or more major human serum HSV-neutralizing antibodies is modified to reduce or eliminate binding of the virus particle to a major human serum HSV-neutralizing antibody such that neutralization of the virus by a major human serum HSV-neutralizing antibody is reduced or eliminated (see e.g. abstract; [0007], [0008], [0035] - [0040]; Table 1; claims 1 and 2). The rHSV can be derived from or engineered from HSV-1 or HSV-2 [0041]. Glorioso et al 2020 further envisages the use of such antigenically stealthed oncolytic HSV in the treatment of (metastatic) cancer ([0033], [0051] -[0060]). The ability of an antibody to neutralize a virus HSV-1 or HSV-2) can be effectively tested using serum from a human population seropositive for HSV, e.g., HSV-1 or HSV-2, and selective for a specific epitope (See, para [0035], [0038], [0041]).
Thus, Glorioso et al 2020 teaches the inventive concept of HSV-antibody resistant oncolytic HSV (HSV-1 or HSV-2), however does not explicitly teach passaging HSV-1 or HSV-2 with immune sera having elevated levels of anti-HSV antibodies.
Highlander et al 1987 teaches monoclonal antibody-resistant (MAR) mutants were selected by escape from neutralization with individual gD-specific monoclonal antibodies (See, abstract and entire article).
Cairns et al 2014 teaches in the serum of HSV infected people the anti-HSV neutralizing antibodies are found to be mainly targeted at two of the virus-encoded glycoproteins-glycoprotein D (gD), gB and gC (See, abstract, table 1). The anti-gB and gD neutralizing antibodies in the antiserum would reasonably be expected to mutate the neutralizing epitopes on gB and gD glycoproteins to develop neutralization resistant or neutralization escape mutant of HSV virus (HSV-1 or HSV-2).
Rojas et al 1992 is in the virology art and teaches passage (up to 30 passages) in cell culture of FMD type O virus in presence of polyclonal antiserum against the virus. After a limited number of passages under selective pressure, the virus population showed the following characteristics: (1) increased resistance to neutralization by polyclonal antiserum (APS); (2) altered electrophoretic mobility of structural viral proteins (VP1); (3) remarkable plaque size reduction, (4) a pronounced thermosensitivity (ts); and (5) decreased pathogenicity for mice, in both uncloned and cloned small plaque size populations. This indicates that FMDV populations under antibody pressure in vitro, have acquired, in addition to expected characteristics of natural FMDV variants (resistance to neutralization and altered viral structural proteins), phenotypic markers which correspond to attenuated, less virulent variants (See, abstract, Figures 1-4, entire article). Thus, Rojas et al 1992 teaches a method and concept of passaging a virus (FMDV type O) in specific anti-viral serum (anti-FMDV type O) comprising antibodies that specifically bind to a virus (FMDV type O) and results in generation of neutralization escape or neutralization resistant mutant virus. Therefore, Rojas et al 1992 method is appliable to the instant claimed oncolytic HSV (HSV-1 or HSV-2) invention with applicable and required modifications that are within the skills of the ordinary in view of the prior art availability and knowledge in the art.
Lewis et al 1982 teaches hyperimmune serum against HSV-2, and neutralization of HSV-2 virus (See, abstract, page 276 col 2, table 2).
Wakimoto et al 2002 teaches in rats, both natural immunoglobulins and mannan-
binding lectin (MBL) activate complement against the oncolytic HSV, while in mice only MBL is relevant to this activation. However, in humans only natural immunoglobulins play a role in complement activity (See, abstract, entire article).
It would have been obvious to one of ordinary skill in the art to modify the prior art teachings of Glorioso et al 2020 with additional teachings of Highlander et al 1987 on selection of monoclonal antibody-resistant (MAR) mutants by escape from neutralization with individual gD-specific monoclonal antibodies and teachings of Cairns et al 2014 on naturally HSV infected human polyclonal serum comprising antibodies against gB, gC, gD and gH glycoproteins epitopes, and teachings of Rojas et al 1992 on passage of FMD virus and development of neutralization resistant / escape mutants strain for some or major epitopes to arrive at the invention of claim 1. In view of the combined prior art teachings of Glorioso et al 2020 and Highlander et al 1987, Cairns et al 2014 and Rojas et al 1992 it is within the skills of ordinary based on the prior art knowledge in virology to obviously use anti-HSV-1 or anti-HSV-2 polyclonal serum to select neutralization resistant mutants HSV-1 or HSV-2 to arrive at the invention of claims 1 and 5 to develop a efficacious oncolytic HSV-1 or HSV-2 composition with a reasonable expectation of success.
The combined prior art teachings as applied to claim 1 above renders obvious the instant claim 1. One of the ordinary skills in the art would have been motivated to apply the combined prior art teachings as applied to claims 1, and 5 to develop a HSV virus (HSV-1 or HSV-2) that escapes neutralization accounting for mutations in the epitope due to selection pressure of the specific antibodies (neutralization escape mutant HSV) as compared to the wild type HSV seed virus from which the mutant virus (HSV-1 or HSV-2 antibody neutralization resistant mutant) has been derived for obtaining the antibody neutralization resistant mutant HSV virus for developing an efficacious oncolytic virus and for commercial success. There would have been a reasonable expectation of success given the applied combined prior arts teachings and required research skills available with one of the ordinary skills in the art.
Additional teachings of Lewis et al 1982 on rat hyperimmune serum against HSV-2, and
Wakimoto et al 2002 teaching that in rats, presence of both natural immunoglobulins and mannan-binding lectin (MBL) activate complement against the OV, while in mice only MBL is relevant to this activation. However, in humans only natural immunoglobulins play a role in complement activity. These teachings of Lewis et al 1982 and Wakimoto et al 2002 in combination to the prior art teachings applied to claim 1 above would result at the arrival of inventions of claims 8-10. One of the ordinary skills would be motivated to combine rat and mouse serum for the breadth of the neutralizing activity and properties of the rat serum (See, Wakimoto et al 2002) for developing an efficacious neutralization resistant HSV (HSV-1 or HSV-2) as an oncolytic virus for better efficacy and for commercial success. There would be a reasonable expectation of success based on the applied prior arts.
Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 1, 5, and 8-10. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
13. Claims 2-4, and 6-7 are rejected under 35 U.S.C. 103 as being unpatentable over combined prior art teachings of Glorioso et al 2020 (WO2019232379A1, 12/05/2019), Highlander et al 1987 (J Virol. 1987 Nov;61(11):3356–3364), Cairns et al 2014 (J Virol 88, 2014, 12612-22), and Rojas et al 1992 (Journal of virology, 66(6), 3368-3372), Wakimoto et al 2002 (Molecular Therapy, 5(3), 275-282), and Lewis et al 1982 (Journal of Virology, 42(1), 275-282) as applied to claim 1 above, and further in view of Fu et al 2018 (Oncotarget. 2018 Oct 2;9(77):34543-34553), Campbell et al 1992 (Cancer Research, 52 (19), 1992, page 5416-5420, disclosed Human CD47 extracellular domain amino acids 19-141 GenBank ID: Q08722 version Q08722.1), and Polcicova et al 2005 (J Virol. 2005 Sep;79(18):11990-2001).
Claims 2-4 and 6-7: The combined prior art teachings of Glorioso et al 2020, Highlander et al 1987, Cairns et al 2014, Rojas et al 1992, Wakimoto et al 2002, and Lewis et al 1982 as recited supra teaches claim 1. However, does not teach the added limitations of claims 2-4 and 6 on CD47 domain insertion in N-terminus of a glycoprotein, and claim 7 the oncolytic HSV-1 or HSV-2, having an extracellular CD47 domain, is free or substantially free of gE.
Fu et al 2018 is in the art and teaches the added limitations of claims 2-4 and 6 by disclosing HSV encodes several glycoproteins that are assembled on the surface of viral envelope. They include glycoprotein C (gC), gB, gD, gH and gL. Each of them can serve as a candidate molecule for incorporating the extracellular domain (ECD) of murine CD47 (mCD47) so that it may be engrafted to the surface of the virus envelope. We decided to choose gC, as
unlike other glycoproteins mentioned, it is not essential for virus infectivity. As such, modifying it for incorporating mCD47 would not run the risk of altering the natural tropism of the oncolytic virus. The details of virus construction strategy are illustrated in Figure 1. We
initially inserted the ECD of murine CD47 (mCD47, aa 19–161) to the N-terminus of gC to create the chimeric form of gC (cgC), and its expression is driven by CMV IE promoter incorporating mCD47 would not run the risk of altering the natural tropism of the oncolytic virus. The details of virus construction strategy are illustrated in Figure 1. We initially inserted the ECD of mCD47 (aa 19–161) to the N-terminus of gC to create the chimeric form of gC (cgC) (See, abstract, page 34544 col 1 Virus modification strategy, Fig 1, page 34544 col 1 Results- virus modification strategy, entire article).
Campbell et al 1992 teaches Human CD47 extracellular domain amino acids 19-141, disclosed in GenBank ID: Q08722 version Q08722.1, and Fig 3D on page 5419. It would have been obvious to use Human CD47 extracellular domain amino acids 19-141 of Campbell et al instead of murine CD47 extracellular domain 19-161 disclosed by Fu et al 2018 so that the oncolytic HSV is compatible for oncolytic therapy with human immune system in in human patients.
Polcicova et al 2005 teaches added limitation of claim 7 that the extracellular domain of Herpes Simplex Virus glycoprotein E (gE) is indispensable for efficient cell-to-cell spread (See, abstract, entire article). Therefore, it would have been obvious to develop an oncolytic HSV that lack or is substantially free of gE so that the virus does not spread cell-to cell and would offer greater safety of the patients or subjects during the oncolytic therapy (See, abstract, entire article).
It would have been obvious to one of ordinary skill in the art to modify the combined prior art teachings of as applied to claim 1 with additional teachings of Fu et al 2018 on murine CD47 extracellular domain, Campbell et al 1992 on human CD47 extracellular domain amino acids 19-141 and Polcicova et al 2005 on gE extracellular domain of HSV to arrive at the inventions of claims 2-4, and 6-7. One of the ordinary skills in the art would have been motivated to modify the prior art teachings applied to claim 1 with Fu et al 2018 teachings on development of an HSV-CD47 oncolytic virus (HSV-1-CD47 or HSV-2-CD47) to genetically engrafting a murine CD47, a “don’t eat me” signal molecule, to the membrane envelope of an oncolytic herpes simplex virus (HSV) gC glycoprotein to enable it to escape from the mononuclear phagocyte system (MPS) for systemic delivery, and Campbell et al 1992 teaches human CD47 extracellular domain amino acids 19-141 that is obvious to use to replace murine CD47 of Fu et al 2018 with human CD47 of Campbell et al 1992 for human immune system compatibility of the oncolytic HSV, and Polcicova et al 2005 teaches the extracellular domain of Herpes Simplex Virus gE is indispensable for efficient cell-to-cell spread and therefor it would have been obvious to remove extracellular domain of gE protein from HSV to prevent cell-to-cell spread and develop a safer oncolytic virus and for commercial success. There would have been a reasonable expectation of success given the applied combined prior arts teachings and required research skills available with one of the ordinary skills in the art. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 2-4, and 6-7. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
14. Claim 11-12 are rejected under 35 U.S.C. 103 as being unpatentable over combined prior art teachings of Glorioso et al 2020 (WO2019232379A1, 12/05/2019), Highlander et al 1987 (J Virol. 1987 Nov;61(11):3356–3364), Cairns et al 2014 (J Virol 88, 2014, 12612-22), Rojas et al 1992 (Journal of virology, 66(6), 3368-3372), Wakimoto et al 2002 (Molecular Therapy, 5(3), 275-282), and Lewis et al 1982 (Journal of Virology, 42(1), 275-282) as applied to claim 1 above, and further in view of Zhang et al 2015 (US8986672B2, 03/24/2015).
Claims 11-12: The combined prior art teachings of Glorioso et al 2020, Highlander et al 1987, Cairns et al 2014, Rojas et al 1992, Wakimoto et al 2002, and Lewis et al 1982 as recited supra teaches claim 1. However, does not teach the added limitations of instant claims 11-12.
Zhang et al 2015 (US8986672B2) disclosed a fusogenic mutant Herpes Simplex Virus Type 2 (HSV-2), wherein the fusogenic mutant HSV-2 comprises a modified ICP10 coding region lacking nucleotides 1 to 1204 of an endogenous ICP10 coding region, wherein said fusogenic mutant HSV-2 comprises the modified ICP10 operably linked to an endogenous or a constitutive promoter and expresses a modified ICP10 polypeptide that lacks protein kinase (PK) activity but retains ribonucleotide reductase activity, and wherein said administration provides for selective killing of cancer cells by direct cytolysis and syncytia formation in cells that are susceptible to replication of the fusogenic mutant HSV-2 (See, claim 1). Zhang et al 2015 teaches “FusOn-H2” and the term “FusOn-H2” as used refers to an HSV-2 mutant having a modified ICP10 polynucleotide encoding a polypeptide having ribonucleotide reductase activity, but lacking protein kinase activity (See, col 5-8, Figs 1-8).
It would have been obvious to one of ordinary skill in the art to modify the combined prior art teachings of as applied to claim 1 with additional teachings of Zhang et al 2015 (US8986672B2) on the ICP10 coding nucleotides 1-1204 deletion and retaining ribonucleotide reductase activity and passaging to obtain FusOn-H2 to arrive at the inventions of claims 11-12.
One of the ordinary skills in the art would have been motivated to modify the combined prior art teachings applied to claim 1 with teachings of Zhang et al 2015 to develop an oncolytic HSV-2 of claims 11-12 for selectively killing cancer cells by direct cytolysis and for commercial success. There would have been a reasonable expectation of success given the applied combined prior arts teachings and required research skills available with one of the ordinary skills in the art. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claims 11-12. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
15. Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over combined prior art teachings of Glorioso et al 2020 (WO2019232379A1, 12/05/2019), Highlander et al 1987 (J Virol. 1987 Nov;61(11):3356–3364), Cairns et al 2014 (J Virol 88, 2014, 12612-22), Rojas et al 1992 (Journal of virology, 66(6), 3368-3372), Wakimoto et al 2002 (Molecular Therapy, 5(3), 275-282), Lewis et al 1982 (Journal of Virology, 42(1), 275-282), Fu et al 2018 (Oncotarget. 2018 Oct 2;9(77):34543-34553), Campbell et al 1992 (Cancer Research, 52 (19), 1992, page 5416-5420, disclosed Human CD47 extracellular domain amino acids 19-141 GenBank ID: Q08722 version Q08722.1), Polcicova et al 2005 (J Virol. 2005 Sep;79(18):11990-2001), as applied to claims 1, 2-4, and 6-7 above, and further in view of and Fu et al 2018b (Oncotarget, 2018, Vol. 9, (No. 30), pp: 21348-21358), and Zhang et al 2015 (US8986672B2, 03/24/2015).
Claim 13: The combined prior art teachings of Glorioso et al 2020, Highlander et al 1987, Cairns et al 2014, Rojas et al 1992, Wakimoto et al 2002, and Lewis et al 1982, Fu et al 2018 and Polcicova et al 2005 as recited supra teaches claims 1, 2-4, and 6-7 are incorporated here in entirety along with the obviousness analysis to render obvious the instant claim 13 added limitation, wherein the composition comprises an oncolytic HSV-2, and the oncolytic HSV-2 subject to passaging is FusOn-CD47 oncolytic virus.
Fu et al 2018b additionally teaches comparison of infectivity and spread between HSV-1 (Baco-1) and HSV-2 (Fus-On-H2) based oncolytic viruses on tumor cells with different receptor expression profiles. Baco-1 grows to a higher titer than FusOn-H2 in this subpopulation of
tumor cells, but the FusOn-H2 kills these tumor cells more efficiently than the Baco-1. FusOn-H2 is effective at treating tumors formed from these tumor cells while Baco-1 is completely ineffective. Our results suggest that this subpopulation of tumor cells may be intrinsically resistant to the therapeutic effect of an HSV-1 based oncolytic virus, but they remain sensitive to a HSV-2 based virotherapy (See, abstract, entire article).
Fu et al 2018 teaches an oncolytic HSV-2 based FusON-H2 (See, page 34551, methods) , and oncolytic HSV FusOn-CD47-Luc (See, page 34545, Fig 1).
Campbell et al 1992 teaches Human CD47 extracellular domain amino acids 19-141, disclosed in GenBank ID: Q08722 version Q08722.1, and Fig 3D on page 5419. It would have been obvious to use Human CD47 extracellular domain amino acids 19-141 of Campbell et al instead of murine CD47 extracellular domain 19-161 disclosed by Fu et al 2018 so that the oncolytic HSV is compatible for oncolytic therapy in human patients.
Zhang et al 2015 teaches the term “FusOn-H2” as used herein refers to an HSV-2 mutant having a modified ICP10 polynucleotide encoding a polypeptide having ribonucleotide reductase activity, but lacking protein kinase activity (See, col 5-8, Figs 1-8). Therefore, based on the definition used in Zhang et al 2015, the HSV-2 virus derived from the applied combined prior art teachings to instant claim 13, the oncolytic HSV-2 subject to passaging would be HSV-2 FusOn-CD47.
It would have been obvious to one of ordinary skill in the art to modify the combined prior art teachings of as applied to claim 1 with additional prior art teachings as applied to the instant claim 13 to arrive at the composition the oncolytic HSV-2 FusOn-CD47. One of the ordinary skills in the art would have been motivated to modify the combined prior art teachings applied to claims 1, 2-4 and 6-7 with additional teachings of Fu et al 2018, Fu et al 2018b, and Zhang et al 2015 to develop an oncolytic HSV-2 FusOn-CD47 for efficacious and selectively killing cancer cells by direct cytolysis and for commercial success. There would have been a reasonable expectation of success given the applied combined prior arts teachings and required research skills available with one of the ordinary skills in the art. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 13. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Double Patenting
16. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-11 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 4, 5, 7-8, 13-14, 18-20, and 32-33 of copending Application No. 18/184,568 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the instant claims 1-11, and co-pending reference claims 1, 4, 5, 7-8, 13-14, 18-20, and 32-33 are directed to oncolytic HSV virus (HSV-1 and HSV-2) and comprise development of neutralization escape mutant HSV-1 or HSV-2 by passaging (viral propagation in a susceptible cell culture) in presence of immune serum directed to HSV-1 or HSV-2 or mixture of antiserum against HSV-1 and HSV-2 comprising elevated levels of anti-HSV antibodies. Although, the co-pending reference claims recites limitation HSV vector, the reference application specification para [0062] defines vectors include but are not limited to, plasmids, cosmids, viruses (bacteriophage, animal viruses, and plant viruses). Therefore, in view of the reference application specification, the HSV vector is interpreted as HSV, HSV-1 or HSV-2.
Thus, the instant claims 1-11 are not identical to the co-pending reference claims 1, 4, 5, 7-8, 13-14, 18-20, and 32-33 but as recited supra, they are not patentably distinct from each other.
This is a provisional non-statutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
17. Relevant Prior Arts:
Zhang et al 2018 (US10039796B2, 08/07/2018). Use of mutant Herpes Simplex Virus-2 for cancer therapy.
Zhang et al 2012 (US20120301506A1, 11/29/2012) Oncolytic Virus as an Inducer for Innate Antitumor Immunity. The present invention is directed to the administration of FusOn-H2, an HSV-2 derived oncolytic virus, to treat tumor cells that are resistant to the lytic effect of the virus. Administration of FusOn-H2 induces the patient's innate immune responses to tumor cells via neutrophils, which are able to destroy tumors efficiently when they migrate to the tumor mass. With the induced innate antitumor immunity, FusOn-H2 is effective at eradicating tumors even when it is used at very low doses.
Borrego et al 1993. Distinct repertoire of antigenic variants of foot-and-mouth disease virus in the presence or absence of immune selection. J Virol. 1993 Oct;67(10):6071-9.
Conclusion
18. No claim is allowed.
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/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Primary Examiner, Art Unit 1600